Medical students often learn axioms in order to remember key features of a disorder. The "rule of 10" used to describe pheochromocytomas (pheos) is a good example: 10 percent occur outside the adrenal glands, and of those, 10 percent occur outside the abdomen, 10 percent are malignant, 10 percent are found in patients who do not have high blood pressure, and finally 10 percent are hereditary. The remainder are classified as sporadic, or random in the general population, not connected with a particular syndrome. When pheos are inherited, they are caused by a dominant gene, either alone or as part of the multiple endocrine neoplasia type 2 syndromes (MEN-2A and MEN-2B), von Hippel-Lindau disease (VHL), or in rare cases neurofibromatosis type 1 (NF-1).

An article in the New England Journal of Medicine by Dr. Hartmut Neumann and colleagues has dashed the rule of 10. In his study of a large group of patients with sporadic pheochromocytoma and no family history of pheos, approximately 25 percent had germline mutations of one of the four susceptibility genes for pheo. Now that we have tools to examine the gene itself, we get a very different picture than we had from clinical diagnosis alone.

This rare tumor of the adrenal gland is called a pheochromocytoma (or pheo). When pheos develop outside the adrenal gland they are called paragangliomas or extraadrenal pheochromocytomas. Patients with pheos may have high blood pressure that is difficult or impossible to control. In some rare cases the blood pressure can be low. Patients may have episodic headaches, excessive sweating, and palpitations as a result of the release of stored chemicals, called catecholamines, from the tumor. Left untreated, pheos may lead to a hypertensive crisis, heart arrhythmia, heart attack, or stroke.

When blood and urine tests reveal excess catecholamines, imaging studies of the abdomen usually reveal an adrenal pheochromocytoma. If the adrenal glands are normal, there is likely a paraganglioma among the structures of the sympathetic nervous system in the abdomen, chest, head, and neck. Similar tumors (called chemodectomas) that do not produce catecholamines may occur in the head and neck, including the carotid-body and glomus-jubulare tumors of the 9th and 10th cranial nerves. Even if these do not secrete chemicals, they usually cause a mass effect, such as cranial-nerve palsy and tinnitus or ringing in the ears. Paragangliomas below the head and neck usually present with signs of excess catecholamine production.

In the Neumann study, reviewed cases of a large group of patients from Freiburg, Germany, and Warsaw, Poland, with pheos that did not fit any of the syndromes. These patients were screened for inherited mutations(2) of four genes known to cause pheos: the RET proto-oncogene (MEN-2), the VHL tumor-suppressor gene (VHL), and two genes recently discovered to give rise to pheos and glomus tumors: SDHD and SDHB. Of the 271 patients studied, 66 (or 24 percent of the participants) had mutations in one of these genes.

30 (45%) VHL
12 (20%) RET
11 (17%) SDHD
12 (18%) SDHB

Looking back, most of these patients with VHL or MEN2 had multiple tumors, often outside the adrenal glands, at a young age. 80% of the people with SDHD and SDHB had solitary pheos, and 40% were older than 30 years of age.

Even in the people who did not have a hereditary condition, one of these genes was found to be altered in the tumor tissue of these sporadic cases of pheo.

It is curious that so many factors can give rise to a pheo. We know that the VHL protein regulates the normal degradation of proteins such as hypoxia-inducible factor, which is implication in the response to conditions of low oxygen. SDHD and SDHB are part of the mitochondrial system in the cell which regulates oxygen sensing and signaling. Therefore the connection may be a defect in the oxygen-sensing system.

People with VHL have a 10-20% chance of having a pheo, with significant variations in families, depending where the mutation in the VHL gene occurs.

Neumann recommends that anyone with a seemingly sporadic case of pheochromocytoma be screened for mutations of the RET, VHL, SDHD, and SDHB genes. Earlier diagnosis of a condition like VHL or MEN will help to ensure better outcomes for these patients.

The Neumann study included people from two geographic regions, in order to reduce the effect of ethnic variation in the study. Nonetheless these two patient groups are both white Europeans within a distance of a thousand miles. We do not yet know whether these findings will be found to be consistent in all parts of the world. Hopefully this study will be repeated in other geographies and other ethnic groups.

Nonetheless, physicians should have a much higher degree of suspicion for familial syndromes in patients with apparently sporadic pheo. A young age and multiple extraadrenal pheos are clues that should prompt a physician to obtain a complete family history, a careful physical examination, and possible genetic analysis.

1. As printed in the New England Journal of Medicine, 346:9, May 9, 2002. Reviewing the article by Neumann et all in the same issue, "Germ-Line Mutations in Nonsyndromic Pheochromocytoma," pages 1459-1466.

2. Germline mutations are mutations that occur in the genes of the egg or sperm and can therefore be passed to one’s children.

As printed in the VHL Family Forum 10:3, September 2002. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org.